Amyotropic lateral sclerosis (ALS) is among the most terrible illnesses known to medicine. While becoming increasingly incapacitated (imprisoned) by progressive paralysis, affected individuals remain fully aware of the impact of their disease. Mutations in superoxide dismutase 1 (SOD1) have been identified in a subset of cases of familial ALS (FALS). Our faculty, who have long-standing commitments to studies of ALS and animals models, plan a highly interactive series of investigations designed to clarify the mechanisms of disease in transgenic (Tg) mice with SOD1 mutations. After we demonstrated that some mutant SOD1 compromised enzyme activity in vitro, we suggested that the mutant protein acquires an adverse property that destroys motor neurons. When these mutant proteins are expressed in Tg mice, mutant SOD1 produce a FALS-like disorder. In these mice, we propose: to investigate the charter/evolution of pathology (Specific Aim 1); to assess the effects of mutant protein on axonal transport (Specific Aim 2); to clarify the roles of mitochondrial injury, oxidation/nitration damage, and cell death pathology in these processes (Specific Aim 3); to examine the contribution of excitotoxicity to motor neuron degeneration (Specific Aim 4); to use strategies to determine the effects of specific gene products on disease (Specific Aim 5); and to determine, in axotomy paradigms, whether motor neurons in mutant mice are more vulnerable to injury and whether axonal transection precipitates disease in Tg mice (Specific Aim 6). Information from these investigations will be invaluable to analysis the mechanisms of disease in ALS and for designing future therapeutic interventions in humans.